Cornea characteristics measuring device

ABSTRACT

An apparatus for measuring characteristics of a substance is provided. The apparatus includes a light source to generate light to form an image. A splitter transmits the light from the light source to a first lens, which collimates the light. A second lens receives the collimated light and is adapted to oscillate with respect to the substance and adapted to transmit and focus the light to a focal region within the substance, such that the oscillation will cause the focal region to pass back and forth through the substance and its surfaces/interfaces. A sensor receives light reflected from the focal region and provides a signal indicative of characteristics of the substance at the focal region.

CROSS REFERENCE TO RELATED APPLICATION

The present application is based on and claims the benefit of U.S.provisional patent application entitled “Cornea Thickness MeasuringDevice”, Ser. No. 60/431,085, filed Dec. 5, 2002, and U.S. provisionalpatent application entitled “Cornea Characteristics Measuring Device”,Ser. No. 60/418,958, filed Oct. 16, 2002, the contents of which both arehereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Measurements of characteristics of the eye are useful in providingappropriate eye care. For example, measurements of the eye have beenuseful in refractive surgical procedures, such as LASIK, wherein aportion of eye tissue is removed to enhance vision of a patient.Additionally, measurements are useful in studying the eye and diagnosingeye disorders.

In refractive surgical procedures, the thickness of the cornea is avaluable parameter in determining how much tissue of the eye should beremoved. The thickness of the cornea is also valuable in diagnosis,prognosis, medical & surgical procedures, and monitoring of otherconditions, such as glaucoma. Devices known as pachymeters (oralternatively pachometers) are used to measure the thickness of thecornea.

Corneal haze is another characteristic measured and used in thetreatment and study of eyes. Corneal haze results from an alteration ofcorneal transparency, which may negatively impact vision. Many eyedisorders such as macular corneal dystrophy, bullous keratopathy,keratoconus, lumican deficiency (in mice), fungal infection andendothelial injury are thought to contribute to corneal haze.Additionally, haze may form after surgical procedures or injuries.

One device that measures characteristics of the eye is an ultrasonicprobe. Ultrasonic probes use sound waves to obtain measurement data,typically a measurement of the thickness of a cornea at a particularpoint. The probes generally contact the cornea during measurement,causing discomfort to the patient. Further, the measurement processusing an ultrasonic probe may require several minutes if multiplemeasurements are necessary to achieve accurate results. The accuracy ofultrasonic pachymetry is also dependent upon accurate knowledge of thespeed of sound in corneal tissue, which may range from 1200 to 2000meters per second in different eyes. Finally, it is difficult to assureperpendicularity of the measurement axis to the corneal surface. Lack ofperpendicularity may result in erroneously large measurements.

Another device that measures characteristics of the eye is a cornealconfocal microscope. A confocal microscope illuminates a small region ofa substance, such as a cornea, with a collimated light source focusedthrough an objective lens to a tiny volume of space at the focal regionof the lens. A detector that is “confocal” with the focal volume detectsany backscattered or reflected light from the focal region. A viewablehistological image is formed by a confocal microscope. One disadvantageof confocal microscopes is that they are extremely expensive andcomplex. Thus, confocal microscopes are not readily available to providemeasurements of an eye. In addition, confocal microscopes are big, bulkydevices that may be difficult to maintain, align, and transport. Theconfocal microscopes also cause patient discomfort due to the fact thatthe lens of the microscope contacts the cornea and the light source ofthe microscope is bright. The measurement time can last several minutes.

In a corneal confocal microscope, signals detected by the detector formimages that may be analyzed to measure the thickness or opacity of thecornea and may further be used to generate a topographical ortomographical image of the cornea. Images taken of a cornea using aconfocal microscope can also provide a visual representation of cornealhaze.

As one might imagine, a system of quantification of corneal haze isuseful in diagnosis and in assessment of various experimental treatmentsor prevention protocols. Many such methods for haze quantification havebeen developed. Clinically, haze is evaluated by “slitlamp” examination,ranked on a scale from 0 to 4 with 0 being normal and 4 being quitesevere. However, this scale is subjective and only coarsely defines theamount of corneal haze.

As a result, it is desirable to have a low cost device that can measurevarious characteristics of the eye, such as thickness and haze.Furthermore, a standardization of corneal haze is desirable to furtheraid in experimentation, reporting, and analysis of corneal haze.

SUMMARY OF THE INVENTION

An apparatus for measuring characteristics of a substance is provided.The apparatus includes a light source to generate light and acollimating lens to collimate the light. In one embodiment, a pattern ofmultiple measurement points are formed from the light. A filter such asa hologram or grating can be used to form an image of several pointsfrom the light via interference effects. An arrangement of pinholes canalso be used to create a source image of multiple points forsimultaneous measurement of multiple focal regions.

A fixed lens collimates light from the filter. An objective lensreceives the collimated light and is adapted to focus light in anoscillatory manner. In one embodiment, the objective lens is adapted tooscillate with respect to the substance under analysis and to transmitand focus the light into the substance (or to the highly reflectivesurfaces and interfaces of the substance as scanning of the focal regionproceeds). A portion of the light reflected from the focal region orregions in the substance is then effectively re-collimated by theobjective lens and directed along the original path, in the reversedirection, then partially deflected (through use of a beam splitter orfiber-optic couplers). This reflected light provides a signal indicativeof characteristics of the substance at the focal region (or focalregions, if a hologram and multi-sensor array are used to simultaneouslyanalyze multiple points). The portion of the light reflected from pointsother than the focal region is rejected through use of an appropriatespatial filter, according to the confocal principle.

Also, as another aspect of the present invention, a method is providedfor quantitatively measuring characteristics of a cornea. The methodincludes generating light and collimating the light with a first lens.The light from the first lens is focused into a focal region of thecornea with a second lens. A portion of light reflected from the focalregion is sensed and a signal indicative of the portion of lightreflected is provided.

To quantify corneal haze, a series of standard reference solutionshaving known turbidity values are measured with the device, with theknown turbidity of each corresponding to the measured signal strength.Next, or in the alternative before the foregoing, a measurement of theturbidity of the cornea is taken using the same device under the sameoperational parameters in a timeframe in which the operationalcharacteristics of the instrument may be assumed to be constant. Afterall measurements are taken, the measurements are analyzed and compared,and the turbidity of the cornea is assigned a value according to theappropriate interpolation of its signal strength compared to thestandard turbidity scale from the standard solution measurements.

In yet another aspect of the present invention, a kit of secondarystandards appropriate for the given device are provided so that correctinstrumental calibration may be verified more conveniently in a settingless amenable to the primary standard, such as a clinic. The secondarystandard kit samples may also serve as standards for characteristicsother than haze, such as thickness. For example, plates may be of acertain thickness and/or opacity to provide simultaneous calibration formeasurement of both properties.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a device according to the presentinvention.

FIG. 2 is a schematic view of an actuator according to the presentinvention.

FIG. 3 is a plot of various measurements taken of a cornea.

FIG. 4 is a schematic view of an alternative embodiment of the presentinvention.

FIG. 5 is a diagram of a plurality of measurements taken of a cornea.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A device 10 as schematically illustrated in FIG. 1 can be assembled inorder to provide a signal indicative of the thickness and/or opacity ofa sample 12. Device 10 includes a light source 14 (herein a visiblediode laser, but the light, which is defined herein broadly aselectromagnetic radiation, could be visible and/or non-visible, coherentand/or non-coherent) that passes light first through a filter 15, suchas a pinhole, hologram or other suitable means of image generation asnecessary, to create an image (for example, three points arranged as thevertices of an equilateral triangle). Any type of image or number offocal spots can be used as discussed below. The light produced by lightsource 14 may be emitted from diode lasers, visible and/or white lightemitting diodes or infrared emitting diodes, or traditional light bulbs,for example.

The light then passes through a splitter 16 that deflects a portion ofthe light. Splitter 16 illustratively may be a beam splitter cube, fiberoptic coupler, or other component. Light that has passed un-deflectedthrough splitter 16 then passes through a lens 18, which collimates thelight and transmits it to scanning lens 20. Lens 20 may be the finalobjective lens, or merely the scanning element before a final objectivelens. Actuator 22 is provided to actuate lens 20 such that a high numberof measurements taken along the axis of motion may be obtained in ashort time period and to focus light through the sample 12. In oneembodiment, lens 20 is actuated in a direction toward (and away) fromsample 12 along the axis of the collimated light beam.

It is worth noting that a stationary objective lens can also be used. Inorder to scan through the cornea, an objective lens with a highchromatic aberration characteristic should be used and the light sourceshould provide light with varying frequencies that are refracted todifferent focal points in the sample. Additionally, a multi-elementdetector adapted to detect the light at different frequencies should beused. In an alternative embodiment, a grating-prism combination (knownas GRISM) can be used to scan through the cornea.

Light that reflects from a focal region within sample 12 is reflectedback to reflector 24 within splitter 16. Reflector 24 then reflectslight onto sensor 26 to sense parameters of the reflected light. Forexample, sensor 26 can include an appropriately small active element orany detector or detector array with proper spatial filtering for theoriginal light configuration from light source 14. Sensor 26 provides asignal (or signals) indicative of thickness and/or opacity of sample 12to signal processing module 28. Signal processing module 28 calculatesthe thickness and/or opacity of sample 12 given the signals receivedfrom sensor 26. A display 27 or other rendering device can be coupled tothe signal processing module 28 and is adapted to display an output ofthe calculation from signal processing module 28.

In one embodiment, the lens 18 and/or 20 is a plastic aspheric lenssimilar to those originally designed as a collimation and objective lensfor diode laser sensing applications, particularly CD-ROM heads andlaser pointers. A wide selection of low-cost plastic lenses areavailable. These lenses are helpful for two reasons. First, the low massof the plastic lens enables high-frequency scanning, in the range oftens to hundreds of Hertz. This feature can be important in a hand-helddevice, since the measurements can be taken on a time scale where littlerelative movement occurs between the operator's hand, the instrument,and the cornea. Second, these optimized aspheric lenses have the highnumerical apertures that provide successful confocal optical sectioning.

The axial resolution of confocal optics is largely governed by acharacteristic of the lens known as the numerical aperture (NA). Anysize NA may be used, although axial resolution may be compromised. Withwell-engineered detector circuitry, a lower NA lens may be used. A highNA lens provides increased resolution, although one drawback of high NAlenses is the shorter working distance (WD). In one embodiment, a devicewith an approximately 3 mm working distance can be achieved with a 0.47NA lens, while an approximately 8.3 mm WD can be met with a 0.22 NAlens. This working distance is an improvement compared to contactultrasound instruments, as well as current confocal instruments, whichrequire much more complex objective lens assemblies to achieve theirprimary function, histologic imaging.

A suitable feedback mechanism can be employed in order to notify anoperator of the device that the device is in a suitable range ofoperation corresponding to the working distance. For example, thefeedback can be audio or visual based on the signals detected by sensor26. Signal processing module 28 can provide appropriate feedback to theoperator when reliable signals are received from sensor 26. If theobject to be measured is outside the working distance of the device,unreliable or weak signals will be received by sensor 26.

In another embodiment of the present invention the objective tip of theinstrument could be integrated into an applanation instrument forsimultaneous or nearly simultaneous measurement of corneal thickness andintra-ocular pressure by a form of tonometry. Providing pressure andthickness measurements in the same instrument would save time and alsoaid in developing a correlation between pressure and thickness,particularly with regard to diseases such as glaucoma.

Actuator 22 can be a mechanical oscillator driven by an electroniccircuit. In one embodiment, as illustrated in FIG. 2, the actuator 22includes a drive circuit 30 that provides a signal to scan lens 20 at arate of more than 100 Hz via electromagnetic force interaction. Thespeed of mechanical oscillation is governed by mechanical and physicalcharacteristics of the scanning mechanism. Higher speeds are, ingeneral, desirable, if the data acquisition system can support rapiddetection. Drive circuit 30 includes an oscillator control, for examplea 555 timer, and an output transistor to drive a coil 35. Alternatively,the oscillator control might provide an initial kicking impulse to thecoil, and then rely on an electromagnetic triggering scheme incorporatedinto an armature coupled to the lens 20, to provide reliable,self-calibrated harmonic resonant oscillation. This scanning allows thedevice 10 to yield many data points in a short period of time (measuredin seconds or fractions of a second). As lens 20 moves axially withrespect to the collimated light, the focal point of the lens 20 movesthroughout the sample 12.

As previously stated, the device is able to scan the objective lens 20along the axial dimension at a frequency of tens to hundreds of Hz, overa distance of millimeters. This scanning is easily accomplished bymounting the lens 20 on an armature 32 such as a piece of spring-steelor similar material, and then “kicking” the oscillator at its naturalfrequency through use of an electromagnetic coil 35 driven by drivecircuit 30 and an attached permanent magnet 36. Instead of a singlearmature, a design with multiple parallel armatures could be used toincrease the linearity of the scanning translation motion.Alternatively, other spring types may be used, such as coil springs orbellows springs. Different spring geometry may be advantageous to alterscanning speed, device geometry, or the ease with which the device maybe manufactured, assembled, and aligned. While other arrangements, suchas a voice coil motor, a rotational motor and camshaft mechanism, or apiezoelectric actuator are possible, the spring scanning arrangement issimple and stable, similar to a tuning fork. It is simple andinexpensive to build the circuits to accomplish the scanning, as thecomponents are largely similar to simple components found in audiocircuits or electro-mechanical clocks. Audio signals have been used tofind the resonance frequency of a particular arrangement, and simplesquare-wave oscillators have also been used. These circuits are based ona 555 timer IC and a small output transistor that controls current flowthrough the voice coil, but more sophisticated forms of pulse codemodulation are possible. An electromagnetically-driven scanner has theadvantage of cost, tunability, simplicity, reliability, speed, and lowpower consumption necessary for a hand-held device.

The physical position of the scanning armature 32 may either bemonitored and recorded as a separate data track (via optical, magnetic,capacitive, Hall effect sensor, or any other means), or simply be awell-characterized motion achieved through precision manufacture andverified through measurement of an object of known thickness. A suitableposition sensor 29 may be provided to measure the position of lens 20and provide an output indicative of a position of lens 20 to signalprocessing module 28. When device 10 scans through the sample 12, inparticular a cornea, regions corresponding to front and back surfacesare bright and reflective. Images received by sensor 26 correspond todifferent brightness values.

When the value or values are plotted as a function of focal depth, acharacteristic curve as illustrated in FIG. 3 results. The curve can berepresentative of a single scan or multiple scans that are averaged. InFIG. 3, both the epithelium (the outermost layer of cells of the cornea)and endothelium (the innermost layer of the cornea) produce relativelylarge peaks, illustrated as peaks 40 and 42, respectively. A distance 44between peaks 40 and 42 provides an accurate measurement of cornealthickness when the movement and optical characteristics of the scanningmechanism that generated the signal are known. In one embodiment, signalprocessing module 28 is a computer that includes an algorithm to computethe height and position of the peaks. The signal processing module 28may provide results on display 27. As appreciated by those skilled inthe art, analog circuitry or combinations of analog and digitalcircuitry can be used for signal processing and pre-processing.Furthermore, signal processing module 28 may be embodied in aconventional computing environment that collects, stores and analyzessignals received from sensor 26.

If desired, an arrangement of three or more fiber optic tips may be usedas light source 14, which creates three or more signals. A similar imagemay be achieved with a hologram or a pinhole array. For example, a lightdelivery system with a fiber optic tip serves as both the light source14 and the sensor 26. The fiber optic tip as light source 14 and sensor26 provides a rugged, self-aligned design, and the beam splitter mayalso be replaced by a fused fiber coupler in this embodiment. In oneembodiment, a multimode fiber having a 62 micron core is used. Anotherembodiment uses a single mode fiber having an 8 micron core.

FIG. 4 illustrates a schematic view of a device 50 using a fiber opticcoupler 51 as the light source and detector. In one embodiment, a fusedfiber optic coupler can self-align the light source and detector in asingle component to assure that the light source and detector areconfocal. A rugged, single component additionally prevents disruption ofthe alignment during operation. Components in FIG. 1 are similarlynumbered in FIG. 4. In the embodiment illustrated, three fiber-coupledlaser diodes 52, 54, 56 emit light to three 2×1 fiber splitters 58, 60and 62, respectively. Undeflected light from splitters 58, 60 and 62 ispassed through fibers (which serve as pinholes) to fixed lens 18. Lightfrom the splitters are focused on three spots (that can form apices ofan equilateral triangle) within sample 12, while lens 20 focuses thefocal spots through sample 12. Light reflected from sample 12 isdetected by three fiber-coupled photo detectors 64, 66 and 68 coupled tosplitters 58, 60 and 62, respectively. The photo detectors 64, 66 and 68provide signals to signal processing module 28. A relative phase errorbetween return signals sensed by the detectors can be used to determinethe angle at which device 50 is held. Calculations can then be made bysignal processing module 28 to correct for the angle at which the device50 is held.

Three-dimensional multiple point measurement (3d Triangulation) is anadvantage over ultrasound technology. Instead of simply using one focalspot, three or more focal spots can be synchronously focused in anoscillatory manner through the cornea. Three plots (70, 72 and 74) areshown in FIG. 5, as might be generated by oscillating the three focalspots through sample 12 at a skewed angle relative to the surface normalvector. The optics are such that the spots form the apices of anequilateral triangle in three dimensional space, thereby defining aplane. If the axis of the objective scanning is normal (perpendicular)to the plane of the cornea, the three signals will be in phase. If,however, the probe is not in perfect alignment (as one might expect in ahand-held device), a simple trigonometric equation allows the device tocalculate the angle at which the probe is held using the phase error ofthe three signals (appropriately mapped back to Cartesian spaceaccording to their motion characteristics) and the known spacing of thefocal points in three dimensional space, which then further allows theproper corneal thickness to be calculated.

Ultrasound probes suffer from the fact that misalignment duringmeasurement can yield widely varying results. In order to create the“three spot pattern” or some similar illumination geometry, one mayemploy either common gratings or a computed or traditionally generatedholographic mask. Such technology is inexpensive, and would result inclean patterns while minimizing the “wasted light” from the lightsource. Computed holographic masks could easily form greater than ½ thebeam energy into three perfectly spaced spots, or some other suitablegeometry. If a “custom mask” is prohibitively expensive, twoperpendicular gratings may be used to create a 3×3 grid pattern, andsimilar results achieved with a modified algorithm. Finally, a hologramlaser, which is an integrated optical device used in optical datareaders consisting of a diode laser, hologram image formation component,beam splitter, and light sensor, could be used to consolidate variousseparate components of the device and reduce the size of the device andreduce the cost associated with alignment difficulty of the variouscomponents.

It will further be appreciated that the intensity of signals receivedfrom a sample 12 can be interpreted as a measurement of turbidity of thesample, which can be compared to a measurement of a standard material toquantify an amount of haze present in a cornea. Healthy corneas arequite transparent and only scatter approximately 2% to 10% of incidentlight across the visible spectrum. Corneal haze is thought to be theresult of incongruities in the cornea, which causes an increase in theamount of scattered light in the cornea. Referring to FIG. 3, therelative intensity of data points between peak 40 and 42 may beextracted in order to provide a relative measurement of the turbidity ofsample 12. The relative measurement can be compared to a substancehaving a known turbidity. As a result of the comparison, a quantifiedmeasurement of haze in sample 12 results. Accordingly, an objectivequantified value of haze can be determined.

A standardized substance may be used having a known turbidity tocalibrate devices 10 and 50. For example, a set of calibrating plateshaving known turbidity values can be used to perform the calibration.After calibration has been performed, signal processing module 28 caninterpret signals received from devices 10 and 50 in order to provide arelative output using values obtained from the calibration plate.Calibration of thickness measurement may also be achieved by using asubstance (such as a plate) having a known thickness. A kit includingseveral reference plates of known parameters such as opacity andthickness is useful in providing an easy way to calibrate devices 10 and50.

In one embodiment, a calibrated reference solution such as formazinpolymer suspension of known concentration is measured with theinstrument, and this measurement is then compared to measurements of thecornea to provide reproducible results of the amount of haze in acornea. Varying amounts of formazin turbidity may be used as referencevalues to quantify corneal range. For example a range of 0–4000Nephelometric Turbidity Units (NTU) for formazin may be used as aprimary standard in the development of a secondary standard of hazemeasurements.

Although the present invention has been described with reference topreferred embodiments, workers skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention.

1. An apparatus for measuring characteristics of a substance,comprising: a light source to generate light; a first lens to collimatethe light from the light source in a direction toward the substancealong an axis; a second lens receiving the collimated light transmittedthrough the first lens and adapted to focus the light into a focalregion in the substance; an actuator operably coupled to the second lensto oscillate the second lens along the axis; a position sensor operablycoupled to the second lens to sense a position of the second lens; and asensor receiving the light reflected from the focal region in thesubstance and providing a signal indicative thereof as a function of theposition of the second lens.
 2. The apparatus of claim 1 and furthercomprising a signal processing module receiving the signal from thesensor and providing an output indicative of properties of the substanceat said focal region.
 3. The apparatus of claim 2 and further comprisinga display coupled to the signal processing module to display the output.4. The apparatus of claim 2 wherein the signal processing module isadapted to provide a feedback signal indicative of an acceptable workingdistance from the apparatus to the substance.
 5. The apparatus of claim2 wherein the output is indicative of a thickness of the substance. 6.The apparatus of claim 2 wherein the output is indicative of an opacityof the substance.
 7. The apparatus of claim 1 and further comprising afilter to form an image pattern of light from the light source.
 8. Theapparatus of claim 7 wherein the image pattern includes at least threefocal spots, spaced apart from one another.
 9. The apparatus of claim 8wherein the sensor receives reflected light indicative of the at leastthree focal spots and wherein a signal processing module is coupled tothe sensor and calculates a relative phase difference of signalsassociated with each of the at least three spots and provides an outputindicative thereof.
 10. The apparatus of claim 1 and further comprisinga beam splitter to partially deflect light from the light source andreflect light from the focal region of the substance to the sensor. 11.The apparatus of claim 1 wherein the second lens is a plastic asphericlens.
 12. The apparatus of claim 1 wherein the light source is a fiberoptic coupler.
 13. The apparatus of claim 1 wherein the light source isa light emitting diode.
 14. The apparatus of claim 1 wherein the lightsource is a laser.
 15. The apparatus of claim 1 wherein a numericalaperture of the second lens is in a range from approximately 0.47 toapproximately 0.22.
 16. A kit comprising the apparatus of claim 1 and atleast one calibration plate having a known parameter to provide areference for calibrating the apparatus.
 17. The kit of claim 16 whereinthe known parameter is a thickness of the plate.
 18. The kit of claim 16wherein the known parameter is an opacity of the plate.
 19. A method ofquantitatively measuring characteristics of a cornea, comprising:generating light; collimating the light with a first lens in a directiontoward the cornea along an axis; focusing the light with a second lensinto a focal region of the cornea; actuating the second lens along theaxis to focus the light into the cornea at a rate equal to or greaterthan 10 hertz; sensing a portion of light reflected from the focalregion of the cornea; and providing a signal indicative of the portionof light reflected.
 20. The method of claim 19 and further comprisingdisplaying the signal indicative of the portion of light reflected. 21.The method of claim 19 wherein the signal is indicative of a thicknessof the cornea.
 22. The method of claim 21 and further comprisingcomparing the signal to a reference signal indicative of a knownthickness.
 23. The method of claim 19 wherein the signal is indicativeof an opacity of the cornea.
 24. The method of claim 23 and furthercomprising comparing the signal to a reference signal indicative of aknown opacity.
 25. The method of claim 19 and further comprisingfiltering the light to form an image pattern of light.
 26. The method ofclaim 25 wherein the image pattern includes at least three focal spots,spaced apart from one another.
 27. The method of claim 26 and furthercomprising receiving reflected light indicative of at least three focalspots and calculating a relative phase difference of signals associatedwith each of the at least three spots.
 28. The method of claim 19 andfurther comprising partially deflecting light and reflecting light fromthe focal region with a beam splitter.
 29. The method of claim 19 andfurther comprising partially deflecting light and reflecting light fromthe focal region with a fiber optic coupler.
 30. The method of claim 19wherein the second lens is a plastic lens.
 31. The method of claim 30wherein the second lens has a numerical aperture in a range fromapproximately 0.47 to approximately 0.22.
 32. The method of claim 19 andfurther comprising providing a feedback signal indicative of anacceptable working distance between the second lens and the cornea.